This invention relates to compositions and methods of enhancing the immune system in warm-blooded animals showing symptoms of antigenic morbidity. More particularly, this invention relates to amino acid chelated mineral compositions containing one or more minerals selected from the group consisting of copper, zinc, manganese, iron and selenium and to methods of administering these compositions to influence mineral uptake and absorption in warm-blooded animals exhibiting symptoms of antigenic morbidity with the resultant strengthening of the immune system of the animal.
Metabolic dysfunctioning in warm-blooded animals may h=indicated by a variety of overt symptoms or signs. General malaise, increased morbidity and/or mortality, poor food conversion and/or loss of weight and sterility, among others, are indications of compromised metabolic functioning. One of the causes of metabolic dysfunctioning is an inadequate immune system brought on or hampered by antigenic morbidity. By "antigenic morbidity" is meant that the health and well-being of the warm-blooded animal is compromised by a disease initiated or worsened due to the presence of an entity displaying an antigen. With the exception of antigens of autoimmune origin, an antigen is a foreign substance, usually a protein or carbohydrate, which, when introduced into the body, provokes an immune system response which stimulates the production of antibodies or immunoglobulins. An inadequate immune system may be the result of insufficient development of the system or the breakdown of the system resulting from viral, bacterial or other antigenic infections. Most antigens of immediate concern are foreign protein or carbohydrate substances such as viruses, bacteria, protozoa and molds. In simple terms, when an entity displaying an antigen enters the body, there is recognition of the antigen by the immune system which stimulates synthesis of circulating antibodies (immunoglobulins) specific to the antigen. Many of these cellular responses are controlled by enzyme systems which have a trace element at their core. Manganese, copper and zinc are examples of co-factors in the enzymes controlling proper immune functioning. Iron and selenium may also play important roles. Iron deficiency is associated with impaired cell-mediated immunity. Investigations with selenium have shown that it can produce stimulatory effects on the immune response.
Viral and other infections sometimes overwhelm the immune system leading to secondary complications which tend to exacerbate the primary infection. For example, some infections cause morphological changes in the intestine which result in malabsorption which may hinder the uptake of the metallic cofactors which are beneficial for immune system functioning. A common site of intestinal abnormality is the duodenum, the portion of the small intestine where metal ions are primarily absorbed under normal conditions. Since the pH in the duodenum is acidic, metal ions are present in soluble ionic form. As these ions pass along the intestinal tract, the pH in the jejunum becomes more basic and absorption of metals in ionic form becomes more difficult. Diarrhea is also a common problem associated with many infections due to the profuse fluid secretion in the duodenum and proximal jejunum resulting in malabsorption of minerals.
An extreme viral infection currently of major concern is popularly referred to as AIDS (acquired immune deficiency syndrome). More appropriately it is an HIV (human immunodeficiency virus) infection leading to AIDS. This disease proceeds through various stages from HIV exposure to HIV infection and on to development of AIDS. These stages are classified by Redfield, et al. in an article entitled "The Walter Reed Staging Classification for HTLV-III/LAV Infection" published in the New England Journal of Medicine, Volume 314, Page 131, January, 1986 and are referred to as the Walter Reed (WR) classification. They are thus referred to as WR0 through WR6. The WR0 classification means there has been exposure to the HIV virus although there are no symptomatic indications. WR1 means there is a positive HIV antibody and/or virus determination but no other symptoms. A WR2 classification is characterized by chronic lymphadenopathy or swollen lymph nodes in addition to positive HIV antibody and/or virus determination. A WR3 classification is reached when the T4-cell count drops below 400 cells per cubic millimeter of blood and stays down. The normal T4-cell count is about 800. There may or may not be chronic lymphadenopathy in WR3 through WR6 classifications but the T4-cell count stays below 400. A patient moves to the WR4 stage after partial sub-clinical (asymptomatic) defects are found in delayed hypersensitivity, i.e. the ability to react to skin tests that are a barometer of immune functioning. The line into WR5 is crossed when the patient completely fails to respond to the skin test or when thrush (a fungal disease of the mouth) develops. Lymphadenopathy and abnormalities of the T4-cell and skin tests must persist for at least three months to serve as valid criteria. Patients enter into the WR6 stage and are said to have AIDS when opportunistic infections, which occur because the immune system has broken down, such as cryptococcal meningitis, develop elsewhere in the body.
The HIV virus is a retrovirus which does not per se cause death of its host. However, the presence of the HIV virus contributes to the decline of T4-cells in the body. The T4 lymphocytes, or T4-cells, recognize foreign antigens or infected cells. Upon recognition, the T4-cells help activate another set of white blood cells called B-lymphocytes. These B-cells then multiply and produce specific antibodies that bind to the infected cells and other organisms containing the antigen. The binding of the antibodies to the antigen displaying cells or organisms inactivates and/or destroys those cells or organisms.
The T4-cells have other functions as well. They orchestrate cell-mediated immunity by killing infected cells with cytotoxic cells such as T8 lymphocytes and white cells known as natural killer cells. The T4-cells also influence mobile scavenger cells known as monocytes and macrocytes. These scavengers engulf infected cells and foreign particles and secrete a variety of cytokines. The cytokines are small but highly potent proteins that modulate the activity of many cell types, including T and B cells. The T4-cells also secrete cytokines on their own which stimulate the proliferation of T and B cells in the body.
T4-cells require the presence of trace minerals for their production. However, in cases of HIV infection, there is malabsorption of cationic minerals which leads to a decrease in the T4-cell production. From the above, it is apparent that the loss of T4-cells can seriously impair the body's ability to fight antigen caused infections and viral infections, in particular. The eradication of these invading organisms requires a highly-orchestrated cell-mediated response. Without T4-cells this immune response does not function satisfactorily.
According to Redfield et al., "HIV Infection: The Clinical Picture," Scientific American, 259:90, October, 1988, there is a balance of power between the HIV virus and the immune system arranged by the T4-cells. From the WR0 (exposure stage) to the WR1 stage the HIV virus increases rapidly at which point the immune system begins to respond. By the time the WR2 stage is reached the viable virus in the body has dropped dramatically with the concomitant rise in scavengers, macrophages, T-cells, B-cells, antibodies and other immune system members. The immune system remains somewhat in control throughout the WR2 and into the WR3 stages although there is a gradual rise in HIV. However, by the time the WR4 stage is reached, the HIV has begun to overwhelm the immune system and the T4-cells become so depleted that the balance of power switches and from that point on, the HIV replicates wildly, overwhelming the remaining T4-cells and any vestiges of immune defense.
The retrovirus pattern shown by the HIV virus in going from stage to stage until the T4-cells are no longer able to function raises unanswered questions. Why is the retrovirus initially dominant at first only to be controlled during the first few stages of the infection? In other words, if the retrovirus is destroying T4-cells in excess of what the immune system has, why does the immune system suddenly become more dominant as the individual moves into the WR2 and even into the WR3 stages? It could be argued that the HIV virus destroyed so many T4-cells that the immune system was no longer able to dominate. However, that argument is flawed in that the retrovirus was dominant in the WR1 stage only to yield to the immune system during the WR2 and WR3 stages and into the WR4 stage. This suggests that the immune system was able to control the retrovirus until such time that some event occurred to the host or the immune system of the host to inhibit the continued control of the retrovirus.
It is known that as the HIV infection progresses from stage to stage, the retrovirus is responsible for morphological changes in the intestine resulting in malabsorption of essential nutrients. While not known for a certainty, it is believed that trace minerals, in particular, are inadequately absorbed. This, in turn, prevents the immune system from regeneration to the degree necessary to continue to fight the onslaught of the retrovirus as the disease goes from stage to stage. As previously stated, manganese, copper and zinc are the primary co-factors in the enzymes controlling proper immune functioning and iron and selenium are also factors which may be necessary. The production of any new cell, including the all important T4-cells, requires DNA and RNA. Zinc is essential for the production of these nucleic acids through activating the enzymes DNA polymerase and RNA polymerase. In the absence of zinc, cell mitosis is blocked.
Heise, et al, "Jejunal Dysfunction Associated with Human Immunodeficiency Virus (HIV) Infections", J. Am. College Nutr., 7:406, 1988, report that the HIV virus causes malabsorption. This is caused in part by abnormal interocyte function as reflected by immaturity, decreased cell density and low enzyme activity. These abnormalities in the intestinal tract are independent of the stage of the HIV infection. Endoscopy of 200 patients treated for HIV infections as reported by Heise, et al., "Gastrointestinal Befunde bei der HIV-Infektion. Klinik, Mikrobialogische Befunde und Endoskopisches Erscheinungsbild", Ptsch. Med. Worchenschr, 113:1588, 1988, revealed that in 60%, there were mucosal changes. Wall, et al., "Multifocal Abnormalities of the Gastrointestinal Tract in AIDS", A.J.R. 146:1, 1986, reported that the most common site of intestinal abnormality was the duodenum which is the portion of the intestinal tract where metal ions are generally absorbed. The mucosal changes noted by Wall, et al, supra, include thickened folds, modularity, increased secretions, superficial erosions, ulcerations, plaque formation and tumor mass. It was further noted that, upon closer examination of the duodenums of patients infected with HIV virus, the infected cells were located in both the crypts and the lamina propria, suggesting that the HIV virus may contribute to some of the gastrointestinal disorders noted above.
One factor which may contribute to the malabsorption syndrome in HIV related illness is that ionic mineral absorption requires an integral protein carrier molecule embedded in and transversing the mucosal membrane. Once absorbed into the mucosal cell the transfer of the cation from the terminal web below the microvilli to the basement membrane requires the presence of carrier proteins. For iron and most minerals apoferritin is a suitable carrier. In the case of zinc, albumin is the carrier protein. For copper the carrier is ceruloplasmin and for manganese it is transmanganin. In some HIV infected patients there is the development of Kaposi's sarcoma, a type of tumor that erupts on the mucosal wall. These tumor cells are derived from membrane cells in the mucosa rather than from the lymph cell. Laine, et al., "Protein-losing Enteropathy in Acquired Immunodeficiency Syndrome due to Intestinal Kaposi's Sarcoma,", Arch. Intern. Med., 147:1174, 1987 report that Kaposi's sarcoma caused a loss of protein and albumin that could have potentially been used to transport metal ions from the small intestine wherever the sarcoma existed, providing further evidence of duodenal malabsorption of minerals in HIV infected patients who have developed this sarcoma. Both protein and albumin are necessary to transport mineral ions from the gut to the plasma.
Similar malabsorption problems are manifest in other species of warm-blooded animals, such as chickens, infected with reovirus as opposed to a retrovirus.
If the immune system is suppressed or does not function properly the chemistry of the cells is altered and the cells do not perform their tasks due to mineral deficiencies.
From the above it is evident proper metabolic functioning of minerals such as copper, zinc, manganese, iron and selenium play an important role in maintaining the immune system. Moreover, it is also evident that there may be metabolic dysfunctioning of cells on the surface of the intestinal lumen to the point that these minerals may not be adequately absorbed in warm-blooded animals, including humans. This could occur if the animal were suffering from antigenic morbidity which affected the portion of the intestine where mineral ions were most likely to be absorbed, i.e. the duodenum. Over a period of time, the inability of the body to absorb these minerals would result in compromising the immune system and allowing secondary diseases to be introduced into the body. It would therefore be beneficial to provide essential minerals to warm-blooded animals exhibiting symptoms of metabolic dysfunctioning due to antigenic morbidity in a bioavailable form in which such minerals would be absorbed via a pathway which did not require duodenal absorption in ionic form.
Ashmead et al., U.S. Pat. No. 4,020,158; Ashmead, U.S. Pat. No. 4,076,803; Jensen U.S. Pat. No. 4,167,564; Ashmead, U.S. Pat. No. 4,774,089 and Ashmead, U.S. Pat. No. 4,863,898 all teach various uses for amino acid chelates in reference to increasing absorption of essential minerals into biological tissues. Some of these patents suggest that certain mineral and ligand combinations can enhance metal uptake in specific organs or tissues where specific biological functions are enhanced, i.e. minerals crossing the placental membranes into foeti, estrus or spermatogenesis, etc. However, it has not heretofore been known that a biological system, as distinguished from tissues, can be affected directly through the proper administration of amino acid chelates. By definition, a system is a set or series of interconnected or interdependent parts or entities (objects, organs, fluids, organisms, etc.) that function together in a common purpose or produce results impossible of achievement by one of them acting or operating alone. Hence, there is greater complexity involved in affecting a system in order to influence or assist in the enhancement, maintaining or strengthening of such a system as compared to influencing mineral uptake or to the direction of minerals to certain tissue sites.